editorial...

Hindawi Publishing CorporationInternational Journal of MicrobiologyVolume 2012, Article ID 326503, 2 pagesdoi:10.1155/2012/326503

Editorial

Antimicrobial Peptides as Therapeutic Agents

Mathew Upton,1 Paul Cotter,2 and John Tagg3

1 Microbiology and Virology Unit, School of Medicine, University of Manchester, Oxford Road, Manchester M13 9PL, UK2 Teagasc Food Research Centre, Alimentary Pharmabiotic Centre, Moorepark, Fermoy, Cork, Ireland3 Department of Microbiology and Immunology, University of Otago, P.O. Box 56, Dunedin, Otago, New Zealand

Correspondence should be addressed to Mathew Upton, [email protected]

Received 5 April 2012; Accepted 5 April 2012

Copyright © 2012 Mathew Upton et al. This is an open access article distributed under the Creative Commons AttributionLicense, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properlycited.

In developing this special issue, we sought to raise awarenessof the potential of antimicrobial peptides (AMPs) for clinicaluse and to highlight recent developments in the field. Theissue contains research articles covering the full spectrumof contemporary work, ranging from the rational design ofsynthetic peptides and discovery of bacteriocins, to testing ofthe efficacy of AMPs in animal models. We have included twoexpert reviews reflecting on the potential of both eukaryoticand prokaryotic peptide antibiotics for clinical use.

The antibiotic development pipeline is devoid of immi-nent solutions to the problems caused by resistant gram-negative bacteria and only a small number of new agentsexist for therapy of infections caused by gram-positives. Thepathway for development of new antibiotics is both long andextremely expensive and, therefore, “big-pharma” has notinvested significantly in this area for decades.

The scarcity of antibiotics to combat infectious diseaseis commonly acknowledged and the specter of untreat-able infections has been widely publicized. However, someadditional potential impacts of the absence of efficaciousantibiotics are not as widely discussed. The inability to reli-ably treat infections could potentially mean that all electivesurgery ceases, and, moreover, there could be significantrestrictions placed on the use of cancer chemotherapy. Thus,in order to maintain anything like the level of medical carethat many of us now enjoy, we must devote considerableeffort to find solutions to this steadily-evolving clinicaldilemma. AMPs appear to merit a prominent position inthe catalogue of pharmaceuticals that should be more ex-haustively investigated in our search for new antimicrobialagents.

Many AMPs have potent activity against bacteria, includ-ing those that are resistant to conventional antibiotics. Their

activity is often relatively-specifically directed against certaingenera or groups of bacteria, which could limit damagingeffects on a patient’s commensal flora. AMPs generallyexhibit high stability to wide ranges in pH and temperature,characteristics that may be beneficial for their scaled-up pro-duction and formulation into deliverable products. Also, dueto their rather specific modes of action, many AMPs exhibitlow toxicity for eukaryotic cells, providing an opportunity fora wide therapeutic window. Their typical mode of action isalso linked to a low propensity for resistance developmentin target bacteria. These unique features differentiate AMPsfrom many conventional antibiotics.

Outside of the potential use of AMPs as alternativesto antibiotics with respect to the treatment/prevention ofdisease, numerous recent reports have also described theactivity of AMPs against bacteria growing in biofilms, that is,communities encased in structured matrices of extracellularmacromolecules, on medical devices. Medical devices canbecome colonized with bacteria growing in biofilms, whichare resistant to elements of the host immune response andto extremely high concentrations of conventional antibiotics.Consequently, resolution of medical device-related infec-tions usually requires the removal of the device. Notably,low concentrations of some AMPs have been shown to haveinhibitory and disruptive properties that can eliminate evenwell-established biofilms.

It is also important to consider the fact that some AMPshave been shown to exhibit immunomodulatory properties;that is, they can reduce the tissue-damaging inflamma-tory response to infection, whilst stimulating antimicrobialimmune activities. Peptides exhibiting modulatory features,as well as overt antimicrobial activity, are now being selectedas favoured candidates for further evaluation in clinical trials.

2 International Journal of Microbiology

Recently, the search for AMPs has benefited from anumber of advances in informatics and peptide engineer-ing strategies. This, coupled with renewed interest frombig-pharma, manifested by some recent acquisitions ofcompanies using natural product screening approaches, isincreasing the prominence of AMPs. This current specialissue includes research articles and reviews that togetherdescribe the process of discovery of AMPs, their testing inin vivo models and outlines steps taken in the developmentof clinically-relevant agents.

The paper by H. Jin-Jiang and colleagues describes thedesign and synthesis of a range of AMPs and reports onthe activity of K11, a 20 mer highly cationic helical pep-tide with activity against gram-positive and gram-negativebacteria, including drug resistant clinical isolates. K11 has ahigh therapeutic index/window and clearly warrants furtherinvestigation. Thus, the paper demonstrates the utility ofsynthetic approaches to the development of novel chimericAMPs.

Also included in the special issue is a report by P. A.Wescombe and colleagues, which focuses on the character-ization of a bacteriocin from the SA-FF22 family producedby members of the Streptococcaceae. The plasmid-encodedpeptide G32 was purified from a culture of Streptococcussalivarius, a species known to include numerous bacteriocinproducers, and is active against the pathogen Streptococcuspyogenes. An interesting feature of this lantibiotic peptideis the apparent absence of an auto-induction capability.The work supports previous suggestions that Streptococcussalivarius mega-plasmids are repositories for lantibiotic lociand that bacteria producing these lantibiotics can be effectiveprobiotics.

C. Piper and colleagues demonstrate the utility of wholeanimal bioimaging approaches to demonstrate that thelactococcal lantibiotic lacticin 3147 could prevent systemicspread of Staphylococcus aureus following subcutaneousdelivery of the peptide. This is important work as it addsto the growing evidence base that suggests that lantibioticsand other AMPs could potentially be used to control systemicinfections, most previous approaches having been restrictedto topical applications.

The two reviews included in this issue elegantly precisrecent advances that have been made with AMPs derivedfrom both bacteria and insects. M. Ntwasa and colleaguesdescribe the medical potential of immune system peptides ofthe coleopteran insects. The authors report that these ancienteukaryotes have a highly developed and robust immunesystem that has contributed to their survival. Exploitationof the immune effectors from these organisms holds greatpotential for use in clinical medicine. The review alsodescribes the utility of databases and full genome sequencedetermination in AMP discovery.

The paper by C. T. Lohans and J. C. Vederas is an exten-sive review of the potential utility of the unmodified, or classIIa, bacteriocins. The paper describes peptide engineeringapproaches for increasing the value of bacteriocins, methodsfor improved in vitro production and efficient purification,various in vivo delivery options and, finally, gives some atten-tion to the important issue of the development of resistance

to bacteriocins. The paper concludes with a positive outlookfor the use of bacteriocins in medical therapy.

We agree that there is great potential for the use of AMPsin clinical therapy for infectious disease, either throughdirect antimicrobial activity or modulation of the immuneresponse to infection. Contributors to this special issue alsodiscuss the possibility for use of some AMPs in antitumortherapy. AMPs offer some significant advantages over con-ventional antibiotics and we are now making importantadvances in the discovery, optimization, and activity testingof these agents. In parallel, publications in this field areattracting the attention of increasing numbers of academicand industrial researchers. It is genuinely an exciting time tobe involved in the development of AMPs and we trust thatthis special issue leaves readers similarly enthused about thesubject.

Mathew UptonPaul Cotter

John Tagg

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